MCFD2 is a soluble EF-hand-containing protein that forms a 1:1 stoichiometric complex with the transmembrane lectin LMAN1 to function as a cargo receptor for ER-to-Golgi transport 1. This LMAN1-MCFD2 complex mediates calcium-dependent, glycosylation-independent transport of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi 1. Recent evidence indicates MCFD2 primarily binds cargo proteins while LMAN1 serves as a shuttling carrier, with MCFD2 capable of recruiting factor V and VIII to COPII vesicle budding sites 2. Beyond coagulation factors, the complex also transports α1-antitrypsin in a glycosylation-dependent manner 3. Loss-of-function mutations in MCFD2 cause combined deficiency of coagulation factors V and VIII (F5F8D), a rare autosomal recessive bleeding disorder with plasma factor levels typically 5-27% of normal 4. MCFD2 mutations are the predominant genetic cause in certain populations 4. Mouse models reveal MCFD2-deficient mice have lower factor levels than LMAN1-deficient mice, suggesting distinct cargo-specific functions 5. Therapeutically, RNAi-mediated inhibition of the LMAN1-MCFD2 complex reduces factor VIII levels and prolongs coagulation time, suggesting potential as an anticoagulant strategy 6.